PROJECT ABSTRACT This K99/R00 Career Development Award will provide the applicant, Dr. Warren Andersen, with the research experience and training to propel her into a career as an independent investigator in the field of genetic and molecular epidemiology with a focus on the interplay between race, modifiable risk factors, and the genetic determinants of cancer risk and outcomes. The research plan uses Mendelian randomization methods to evaluate the hypothesis that circulating and bioavailable vitamin D levels are associated with decreased colorectal cancer risk. Mendelian randomization (MR) methods can be used to evaluate the associations between long-term exposures and diseases by using genetic variants as instrumental variables in place of exposures. Dr. Warren Andersen will also assess whether vitamin D binding protein modifies the association between vitamin D and colorectal cancer risk. The project will leverage resources from three established epidemiologic consortia (the ColoRectal Transdisciplinary Study (CORECT) consortium, a colorectal cancer genome-wide association study consortium among African Americans, and the Asia Colorectal Cancer Consortium) and the Southern Community Cohort Study to evaluate associations in large samples including individuals of European, Asian and African descent. Dr. Warren Andersen will create race-specific genetic scores to represent circulating vitamin D and vitamin D binding protein. Fine-mapping will be conducted to identify potentially causal variants to be included in the vitamin D genetic scores. These genetic scores will then be assessed for associations with overall colorectal cancer risk, and colorectal cancer risk stratified by specific characteristics of the tumor such as COX-2 expression, PIK3CA mutation status, and stage. During the Career Development Award Dr. Warren Andersen will gain additional skills in genetic analysis and increase her knowledge in colorectal cancer biology and health disparities. The findings from this research project will be used to develop and submit two R01 level projects before the completion of the Career Development Award. The additional experience gained from this Career Development Award will prepare Dr. Warren Andersen to be a leader in the field of genetic and molecular epidemiology of cancer, with expertise in colorectal cancer etiology, genetic and cancer epidemiology, and the root causes of racial differences in disease risk. This research topic is of much significance, as the Institute of Medicine's 2010 Report stated, investigation into the causal relationships between vitamin D and total and site-specific cancers is an important research need. The use of MR and molecular epidemiologic methods should provide a more definitive answer to the questions of the relationships of colorectal cancer risk with circulating vitamin D, bioavailable vitamin D and vitamin D binding protein. This study will provide insight into colorectal cancer etiology and potentially identify subgroups of individuals who may benefit the most from vitamin D supplementation.